Alkylated resorcinol derivatives for the treatment of immune diseases

ABSTRACT

The present invention provides a method, compounds, and compositions for treating a disease associated with immune dysfunction. In accordance with the method, a pharmacologically-acceptable composition including at least one compound selected from the group of compounds consisting of 5-alkyl-resorcinol derivatives, cannabinol derivatives, cannabidiol derivatives, cannabigerol derivatives, and combinations thereof is administered to a patient under conditions sufficient to attenuate the dysfunction within the immune system. The invention also provides an antiviral cannabinol derivative that can be used in the inventive method. The invention also provides an alkylated resorcinol derivative and a method of using the alkylated resorcinol derivative to attenuate the growth of a neoplasm. The method and compound are useful for treating diseases of the immune system, such as HIV disease and neoplastic disorders.

This application claims benefit to Ser. No. 60/125,674 filed Mar. 22,1999 and Ser. No. 60/151,595 filed Aug. 30, 1999.

TECHNICAL FIELD OF THE INVENTION

The present invention pertains to a treatment for diseases associatedwith immune dysfunction, particularly HIV disease and neoplasticdisorders.

BACKGROUND OF THE INVENTION

The retroviral Human Immunodeficiency Viruses 1 and 2 (HIV) are the mostcommon causative agents of AIDS. Through a portion of a viral envelopeprotein (gp120), HIV binds specifically and with high affinity to theCD4 molecule on T-lymphocytes. Following binding, the virus fuses withthe cell membrane and is internalized. Within the cell, it produces areverse transcriptase which transcribes its genomic RNA to DNA. Thereverse HIV transcript is then integrated into the cellular DNA where itexists for the life of the cell as a “provirus.” The provirus can remainlatent for an indefinite period of time, or it can be “activated” totranscribe mRNA and genomic RNA, leading to protein synthesis, assembly,new virion formation, budding of virus from the cell surface, and celldeath.

While the precise events triggering activation are poorly understood,they appear to lead to liberation/production of endogenous cellularfactors that interact with the HIV genome to promote translation. Inthis regard, binding of cellular SP1 to the HIV promoter (which containsseveral tandem SP1 consensus binding sites) is needed for high-leveltranscription of the latent HIV genome. Additionally, NFκB functions asa potent transcriptional activator when it binds to one or two(depending on the HIV strain) consensus binding sites in the HIVenhancer, which is adjacent to the promoter. The transcription factorsCREB/ATF, NF-AT, and AP1 also potentiate HIV transcription. As for allretroviruses, the structural and enzymatic gag, pol and env geneproducts are produced when the provirus is activated. HIV firsttranscribes gag-pol as a fusion protein which is ultimately cleaved bythe HIV protease enzyme to yield the mature viral proteins. HIV alsoemploys additional regulatory proteins (specifically the tat and revgene products) as transcriptional enhancers to induce high levels ofgene expression. Nef is another HIV gene that modulates viralreplication levels.

While the set of factors triggering active viral replication remainsonly partially understood, some of them include heat shock, ultravioletradiation, regulatory proteins of other (e.g., superinfecting) viruses,inflammatory cytokines (e.g., IL1, IL2, IL4, IL6, IL10, Tumor NecrosisFactor α (TNFα), Platelet Activating Factor, Interferon γ (IFNγ)), andNitric Oxide. Many of these factors are T-cell activators (e.g., theyprecipitate cell cycling and clonal expansion of T-cell populations),and they are released by many B-cells in direct response to infectiousagents (such as HIV). Such factors also trigger intracellular signalingevents promoting the production of NFκB and its dissociation from itsinhibitor (IkB). Active NFκB is a DNA binding protein activating thetranscription of many cellular genes, and also the HIV genome. In thisregard, cytokines such as TNFα and IL-1 augment NFκB activity incultured T-cells.

Some cells harboring the provirus express HIV gp41, gp120, and possiblyother viral proteins, presumably through basal levels of transcriptionfrom the proviral genome. While a host immune response is mountedagainst such HIV proteins, due in part to the high degree of mutabilityof such proteins and their varied glycosylation patterns, such immuneresponse usually is incomplete, resulting in a pool of latent virus thateffectively avoids immune surveillance. Additionally, the presence ofHIV gp120 in the membranes of infected cells can mediate fusion eventsbetween infected cells and non-infected antigen-presenting cells (e.g.,dendritic cells) via a reaction similar to that by which the virusenters uninfected cells. Rather than destroy infected cells, as might beexpected for a cellular immune response, such fusion events typicallylead to the formation of short-lived multinucleated syncytial “giantcells,” which actually facilitate viral replication. In this regard,while latently-infected monocytes and T-lymphocytes normally arequiescent and have no active NFκB, other cells (e.g., dendritic cells)normally contain high levels of active NFκB. However, dendritic cells donot produce SP1, while T-cells and monocytes express Sp1 in active form.Formation of syncytia between infected T-cells and dendritic cells,thus, brings active NFκB and SP1 into the same cell, facilitatingtranscription of the HIV genome.

The viral life cycle ends when mature HIV are “budded” from the hostcell, retaining some amount of cell membrane as part of its envelope.Oftentimes, these budding events are localized to areas of the cellmembrane where intracellular adhesion molecules (ICAMs) and othersurface receptors coalesce during the cell's activation process. Becausesuch proteins localize to regions of intercellular contact, thisphenomenon (known as polar capping or polarization) can help spread theviral infection by “focusing” viral budding to an adjacent cell or infacilitating syncytia formation. Moreover, liberated virions oftencontain some membrane-bound ICAMs (e.g., ICAM-1), and such viruses canbind cells (e.g., peripheral blood mononuclear cells) throughinteractions not involving the gp120-CD4 interaction. Such ICAM-1⁺ HIVviruses are more infective than ICAM-1⁻ HIV, and since they are cloakedwith the host animal's glycoproteins, they are much less likely to beneutralized by circulating host antibodies. HIV can augment productionof cell adhesion molecules such as ICAM-1 by precipitating thephosphorylation of STAT1α, which binds to the ICAM-1 gene enhancer andpromotes SP1-dependent transcription. Interestingly, inflammatorycytokines (e.g., IFNγ) also precipitate phosphorylation of STAT1α, andthe gene contains consensus binding cites for some of the sametranscription factors involved in HIV replication, notably NFκB.

The presence of latent pools of HIV within quiescent cells, the highmutability of HIV proteins and their relative invisibility to immunesurveillance, and the ability of the virus to alter its tropism byacquiring ICAMs all permit the virus to replicate in the face of anaggressive host immune response. Over time, the virus gradually subvertsand progressively destroys the very system relied on to ward offinfections. This progression of viral persistence and replication is HIVdisease, and it is marked by dysregulation of cytokine signaling,particularly in the lymphatic system, and ultimate destruction of lymphnodes. When HIV disease has progressed to the point where the host'simmune system becomes so incapacitated that it is unable to ward offopportunistic diseases (e.g., bacteria, fungi, neoplasms, etc.), AIDSdevelops. Many patients begin to develop AIDS symptoms when their CD4+T-cell count drops to about 200 (most healthy adults have a CD4+ T-cellcount of about 1000.

To prevent the development of AIDS, many current therapies focus onhalting viral life cycle events, typically by directly targeting viralproteins. For example, gp120 antibodies have been produced in an attemptto block initial cell infection. However, due in part to the ability ofthe virus to spread by syncytia or direct cell-to-cell contact and itsability to acquire ICAM molecules, such attempts have met with mixedresults. Other therapies employ inhibitors of HIV protease to block theformation of mature rep and cap from the rep-cap preprotein. Still otherregimens employ combinations of antiviral compounds, aimed at inhibitingor attenuating viral enzymes. It has been estimated, however, thatspontaneous mutations arise in HIV genes once in about 10⁴ replications(Perelson et al., Science, 271, 1582-86 (1996)). Given that the virustypically undergoes about 10¹⁰ replications each day, resistance toagents acting directly against viral proteins is not uncommon. Moreover,many regimens require a patient to adhere to very a strict dosingschedule involving scores of pills each day. Failure of patients tocomply with such regimens adds to the failure rate of antiviral therapy.In light of these problems, there is a need for new methods, compounds,and compositions for attenuating the progression of HIV disease andother immune dysfunctions.

Many thousands of people are diagnosed with cancer and other neoplasticdisorders each year, and although advances have been made in cancertherapy, the existing treatments are not successful in many cases. Forexample, many anticancer drugs administered to patients often have toxiceffects on non-cancerous cells in the patient's body. Moreover, manyneoplastic cells whose growth can be inhibited by certain drugssometimes become resistant to those drugs. Of course, responsive tumorsrepresent only a small fraction of the various types of neoplasticdisease and, notably, there are relatively few drugs highly activeagainst solid tumors such as ovarian cancer, breast cancer, lung cancerand the like. Thus, patients with many types of malignancies remain atsignificant risk for relapse and mortality. As such, there exists acontinuing need for agents that inhibit neoplastic growth, especiallysolid tumor growth.

BRIEF SUMMARY OF THE INVENTION

The present invention provides a method, compounds, and compositions fortreating a disease associated with immune dysfunction. In accordancewith the method, a pharmacologically-acceptable composition including atleast one 5-alkyl-resorcinol derivative compound selected from the groupof compounds consisting of 5-alkyl-resorcinols, cannabinol derivatives,cannabidiol derivatives, cannabigerol derivatives, and combinationsthereof is administered to a patient under conditions sufficient toattenuate the dysfunction within the immune system. The invention alsoprovides an antiviral cannabinol derivative that can be used in theinventive method. The invention also provides an alkylated resorcinolderivative and a method of using the alkylated resorcinol derivative toattenuate the growth of a neoplasm. The method and compound are usefulfor treating diseases of the immune system, such as HIV disease andneoplastic disorders. These and other advantages of the presentinvention, as well as additional inventive features, will be apparentfrom the following detailed description.

DETAILED DESCRIPTION OF THE INVENTION

In one aspect, the invention provides a method for treating a diseaseassociated with immune dysfunction. In accordance with the method, apharmacologically-acceptable composition including at least one compoundselected from the group of compounds consisting of 5-alkyl-resorcinolderivatives, cannabinol derivatives, cannabidiol derivatives,cannabigerol derivatives, and combinations thereof is administered to apatient under conditions sufficient to attenuate the dysfunction withinthe immune system.

The inventive method is particularly effective in combating HIV diseasein humans, SIV disease in non-human primates, or FIV in feline animals.Without being bound by any particular theory, it is believed that theinventive method promotes quiescence of both actively- andlatently-infected T-cells, monocytes, and macrophages, potentiallythrough a variety of complementing mechanisms. The combination of theseeffects can attenuate the ability of HIV to replicate in a host immunesystem. Absent replication, uninfected components of the immune systemare better able to clear latently-infected cells from the patient, andfewer mutation events occur. Additionally, by attenuating HIVreplication, the method can reduce the probability of interpersonaltransmission, (e.g., perinatal or sexual transmission). Indeed,applications of the inventive method in which the composition isadministered to mucosal tissue (e.g., vaginal or rectal tissue), canretard the uptake of the virus through such tissues, thus reducing theincidence of primary infection. Thus, the invention provides a method ofpreventing the transmission of HIV. Furthermore, the method can guardagainst secondary conditions often attending HIV infection, such asdestruction of lymphatic structure, CNS disease, opportunistic diseases,neoplasms, and the AIDS Wasting Syndrome.

Treatment of HIV disease can be assessed by monitoring the attenuationof its symptoms in response to the continued application of theinventive method. For example, while most healthy adult humans have aCD4+ T-cell count from between about 800 to about 1200, that of HIV+patients steadily declines, as discussed above. Therefore, the inventivemethod pertains to increasing, or attenuating the decrease of, thenumber of CD4+ T-cells (typically by assaying for the CD4+/CD8+ ratio)within an HIV+ patient. For example, through periodic measurements, therate at which a given patient's CD4+ T-cells is declining can beassessed both before and after commencement of therapy in accordancewith the inventive method. Favorable application of the method at leastslows this rate of decrease, and preferably potentiates actual gain inCD4+ cell number. Similarly, the method can decrease, or attenuate theincrease of, viral load (i.e., the titer of circulating HIV) within apatient. Favorable response to the treatment can also be monitored bymeasuring leukocyte adhesion, lymphocyte trafficking, andmonocyte/macrophage mobility (i.e., a chemotaxis assay).

In one embodiment, at least one compound within thepharmacologically-acceptable composition can be a 5-alkyl-resorcinolderivative. Such compounds are advantageous for use in the inventivemethod as they generally exhibit low cytoxicity (see, e.g., U.S. Pat.No. 5,859,067). Exemplary 5-alkyl-resorcinols can have the followingformula:

wherein,

R¹ is:

a) H,

b) a C₁₋₄ alkyl group or ester thereof,

c) COOH,

d) OH,

e) a O—C₁₋₅ alkyl or alkanoyl, optionally substituted by mono- ordi-methylamino or ethylamino groups.

f) a O—CO—C₃₋₁₀ alkyl group containing a carboxyl or amino group,

g)

 wherein n=1 to 8

h) a p-aminobenzyl group or a C₁₋₇ aminoalkyl group or an organic ormineral acid addition salt thereof, an isocyanate or isothiocyanatederivative of the p-aminobenzyl or aminoalkyl group, a carboxylterminated derivative of the aminoalkyl group having from 1 to 7additional carbon atoms or a salt thereof, and an activated derivativeof the carboxyl terminated derivative; or

i) R¹ and R² comprise a substituent of the formula —O(CH₂)₃₋₅, whereinR¹ and R², together with the carbon atoms to which they are bonded,comprises a ring where at least one hydrogen atom thereof is optionallysubstituted with a halogen.

R² is:

a) H, OH or a halogen

b) C₁₋₆ carboxy or alkoxy group, or

c) R¹ and R² comprise a substituent of the formula —O(CH₂)₃₋₅, whereinR¹ and R², together with the carbon atoms to which they are bonded,comprises a ring where at least one hydrogen atom thereof is optionallysubstituted with a halogen.

R³ is:

a) (W)_(m)—Y—(Z)_(n), wherein

W is a C₅₋₁₂ alkyl, alkenyl, alkynyl, group, or mixture thereof,optionally substituted with at least one halogen,

Y is a bond, O, S, SO, SO₂, CO, NH, N(C₁₋₆ alkyl), or NCS,

Z is:

i) a C₅₋₁₂ alkyl, alkenyl, alkynyl, group, or mixture thereof,optionally substituted with at least one halogen, optionally substitutedwith a terminal aromatic ring,

ii) CN₁₋₃, CO₂H, or CO₂C₁₋₄ alkyl, CONH₂, CONHC₁₋₄ alkyl, or CON(C₁₋₄alkyl)₂, wherein each C₁₋₄ alkyl on the amide nitrogen can be the sameor different, or

iii) a phenyl or benzyl group, optionally substituted with halo, C₁₋₆alkyl, C₁₋₆ alkoxy, C₁₋₆ alkylthio, CN, CF₃, CO₂H, or CO₂C₁₋₄ alkyl,CONH₂, CONHC₁₋₄ alkyl, or CON(C₁₋₄ alkyl)₂, wherein each C₁₋₄ alkyl onthe amide nitrogen can be the same or different, and wherein

m and n are the same or different, and each is either 0 or 1,

b) a C₅₋₁₂ alkyl or haloalkyl group, optionally substituted with aterminal aromatic ring, CN₁₋₃, NCS, CO₂H, or CO₂C₁₋₄ alkyl, CONH₂,CONHC₁₋₄ alkyl, or CON(C₁₋₄ alkyl)₂, wherein each C₁₋₄ alkyl on theamide nitrogen can be the same or different, or

c) a C₅₋₁₂ alkene or alkyne group, optionally substituted with ahalogen, ditholene, terminal aromatic ring, CN₁₋₃, NCS, CO₂H, or CO₂C₁₋₄alkyl, CONH₂, CONHC₁₋₄ alkyl, or CON(C₁₋₄ alkyl)₂, wherein each C₁₋₄alkyl on the amide nitrogen can be the same or different;

R⁴ is:

a) H,

b) OH,

c) C₁₋₆ alkoxyl or carboxyl

R⁵ is

a) H

b) a C₁₋₄ alkyl group

c) COOH

d) OH, or

e) a O—C₁₋₅ alkyl (ether) or alkanoyl, optionally substituted with atleast one mono- or di-methylamino or ethylamino group; and

R⁶ is:

a) H or OH;

b) C₁₋₄ alkyl, alkenyl, alkynyl, group, or mixture thereof,

c) O—C₁₋₄ alkyl, alkenyl, alkynyl, group, or mixture thereof, or

d) a pryenyl, gerenyl, or farnesyl group, optionally substituted at anyposition with one or more halogens,

e) (W)_(m)—Y—(Z)_(n), wherein

W is a C₅₋₁₂ alkyl, alkenyl, alkynyl, group, or mixture thereof,optionally substituted with at least one halogen,

Y is a bond, O, S, SO, SO₂, CO, NH, N(C₁₋₆ alkyl), or NCS,

Z is:

i) a C₅₋₁₂ alkyl, alkenyl, alkynyl, group, or mixture thereof,optionally substituted with at least one halogen, optionally substitutedwith a terminal aromatic ring,

ii) CN₁₋₃, CO₂H, or CO₂C₁₋₄ alkyl, CONH₂, CONHC₁₋₄ alkyl, or CON(C₁₋₄alkyl)₂, wherein each C₁₋₄ alkyl on the amide nitrogen can be the sameor different, or

iii) a phenyl or benzyl group, optionally substituted with halo, C₁₋₆alkyl, C₁₋₆ alkoxy, C₁₋₆ alkylthio, CN, CF₃, CO₂H, or CO₂C₁₋₄ alkyl,CONH₂, CONHC₁₋₄ alkyl, or CON(C₁₋₄ alkyl)₂, wherein each C₁₋₄ alkyl onthe amide nitrogen can be the same or different, and wherein

m and n are the same or different, and each is either 0 or 1,

f) a C₅₋₁₂ alkyl or haloalkyl group, optionally substituted with aterminal aromatic ring, CN₁₋₃, NCS, CO₂H, or CO₂C₁₋₄ alkyl, CONH₂,CONHC₁₋₄ alkyl, or CON(C₁₋₄ alkyl)₂, wherein each C₁₋₄ alkyl on theamide nitrogen can be the same or different, or

g) a C₅₋₁₂ alkene or alkyne group, optionally substituted with ahalogen, ditholene, terminal aromatic ring, CN₁₋₃, NCS, CO₂H, or CO₂C₁₋₄alkyl, CONH₂, CONHC₁₋₄ alkyl, or CON(C₁₋₄ alkyl)₂, wherein each C₁₋₄alkyl on the amide nitrogen can be the same or different.

Compounds according to Formula I preferably include OH or OCH₃ as R¹substituents. Preferred substituents at R² are hydrogen, hydroxyl, ormethoxyl groups. Where compounds of formula I are included, preferablyR⁶ is methyl or ethyl. A more preferred compound according to Formula Ihas hydroxyl substituents at R¹, R⁵, and a methyl substituent at R⁶;even more preferably, the compound has a third hydroxyl substituent atR². Preferred substituents at R³ are discussed elsewhere herein;however, the invention provides compounds according to Formula I,wherein R³ is:

a) (W)_(m)—Y—(Z)_(n), wherein

W is a C₅₋₁₂ alkyl, alkenyl, alkynyl, group, or mixture thereof,optionally substituted with at least one halogen,

Y is a bond, O, S, SO, SO2, CO, NH, N(C₁₋₆ alkyl), or NCS,

Z is:

i) a C₅₋₁₂ alkyl, alkenyl, alkynyl, group, or mixture thereof,optionally substituted with at least one halogen, optionally substitutedwith a terminal aromatic ring,

ii) CN₁₋₃, CO₂H, or CO₂C₁₋₄ alkyl, CONH₂, CONHC₁₋₄ alkyl, or CON(C₁₋₄alkyl)₂, wherein each C₁₋₄ alkyl on the amide nitrogen can be the sameor different, or

iii) a phenyl or benzyl group, optionally substituted with halo, C1-6alkyl, C₁₋₆ alkoxy, C₁₋₆ alkyltio, CN, CF₃, CO₂H, or CO₂C₁₋₄ alkyl,CONH₂, CONHC₄ alkyl, or CON(C₁₋₄ alkyl)₂, wherein each C₁₋₄ alkyl on theamide nitrogen can be the same or different,

wherein at least one of W and Z includes a branched chain and wherein inand n are the same or different, and each is either 0 or 1,

b) a terminally-branched C₅₋₁₂ alkyl or haloalkyl group, optionallysubstituted with a terminal aromatic ring, CN₁₋₃, NCS, CO₂H, or CO₂C₁₋₄alkyl, CONH₂, CONHC₁₋₄ alkyl, or CON(C₁₋₄ alkyl)₂, wherein each C₁₋₄alkyl on the amide nitrogen can be the same or different, or

c) a terminally-branched C₅₋₁₂ alkene or alkyne group, optionallysubstituted with a halogen, ditholene, terminal aromatic ring, CN₁₋₃,NCS, CO₂H, or CO₂C₁₋₄ alkyl, CONH₂, CONHC₁₋₄ alkyl, or CON(C₁₋₄ alkyl)₂,wherein each C₁₋₄ alkyl on the amide nitrogen can be the same ordifferent. Many such compounds exhibit antineoplastic activity and canbe employed as such as described herein. While any such compounds can beincluded within the composition in accordance with the inventive method,some preferred compounds are as follows:

As mentioned, compounds according to Formula I can have gerenylsubstituents at R⁶. In this regard, at least one compound within thepharmacologically-acceptable composition can be cannabigerol or aderivative thereof having the following formula:

wherein:

R¹ is:

a) H,

b) a C₁₋₄ alkyl group or ester thereof

c) COOH,

d) OH,

e) a O—C₁₋₅ alkyl or alkanoyl, optionally substituted by mono- ordi-methylamino or ethylamino groups,

f) a O—CO—C₃₋₁₀ alkyl group containing a carboxyl or amino group,

g)

 wherein n=1 to 8

h) a p-aminobenzyl group or a C₁₋₇ aminoalkyl group or an organic ormineral acid addition salt thereof, an isocyanate or isothiocyanatederivative of the p-aminobenzyl or aminoalkyl group, a carboxylterminated derivative of the aminoalkyl group having from 1 to 7additional carbon atoms or a salt thereof, and an activated derivativeof the carboxyl terminated derivative; or

i) R¹ and R² comprise a substituent of the formula —O(CH₂)₃₋₅, whereinR¹ and R², together with the carbon atoms to which they are bonded,comprises a ring where at least one hydrogen atom thereof is optionallysubstituted with a halogen.

R² is:

a) H, OH or a halogen

b) C₁₋₆ carboxy or alkoxy group, or

c) R¹ and R² comprise a substituent of the formula —O(CH₂)₃₋₅, whereinR¹ and R², together with the carbon atoms to which they are bonded,comprises a ring where at least one hydrogen atom thereof is optionallysubstituted with a halogen.

R³ is:

a) (W)_(m)—Y—(Z)_(n), wherein

W is a C₅₋₁₂ alkyl, alkenyl, alkynyl, group, or mixture thereof,optionally substituted with at least one halogen,

Y is a bond, O, S, SO, SO₂, CO, NH, N(C₁₋₆ alkyl), or NCS,

Z is:

i) a C₅₋₁₂ alkyl, alkenyl, alkynyl, group, or mixture thereof,optionally substituted with at least one halogen, optionally substitutedwith a terminal aromatic ring,

ii) CN₁₋₃, NCS, CO₂H, or CO₂C₁₋₄ alkyl, CONH₂, CONHC₁₋₄ alkyl, orCON(C₁₋₄ alkyl)₂, wherein each C₁₋₄ alkyl on the amide nitrogen can bethe same or different, or

iii) a phenyl or benzyl group, optionally substituted with halo, C₁₋₆alkyl, C₁₋₆ alkoxy, C₁₋₆ alkyltio, CN, CF₃, CO₂H, or CO₂C₁₋₄ alkyl,CONH₂, CONHC₁₋₄ alkyl, or CON(C₁₋₄ alkyl)₂, wherein each C₁₋₄ alkyl onthe amide nitrogen can be the same or different, and wherein

m and n are the same or different, and each is either 0 or 1,

b) a C₅₋₁₂ alkyl or haloalkyl group, optionally substituted with aterminal aromatic ring, CN₁₋₃, NCS, CO₂H, or CO₂C₁₋₄ alkyl, CONH₂,CONHC₁₋₄ alkyl, or CON(C₁₋₄ alkyl)₂, wherein each C₁₋₄ alkyl on theamide nitrogen can be the same or different,

c) a C₅₋₁₂ alkene or alkyne group, optionally substituted with ahalogen, ditholene, terminal aromatic ring, CN₁₋₃, NCS, CO₂H, or CO₂C₁₋₄alkyl, CONH₂, CONHC₁₋₄ alkyl, or CON(C₁₋₄ alkyl)₂, wherein each C₁₋₄alkyl on the amide nitrogen can be the same or different;

R⁵ is

a) H

b) a C₁₋₄ alkyl group

c) COOH

d) OH, or

e) a O—C₁₋₅ alkyl (ether) or alkanoyl, optionally substituted with atleast one mono- or di-methylamino or ethylamino group;

R⁶ is:

a) hydrogen,

b) C₁₋₆ alkoxy, C₁₋₆ alkylthio, C₁₋₆ alkyl (preferably ethyl), or C₁₋₆haloalkyl,

c) CN,

d) CO₂H,

e) CO₂—C₁₋₄ alkyl

f) C(Y)(Z)—OH,

g) C(Y)(Z)—O—C₁₋₄ alkyl, or

h) C₁₋₆ alkyl-CO₂—Y,

 wherein Y and Z are each independently H or C₁₋₆ alkyl

R⁷ is:

a) hydroxy (preferably β-hydroxy) or lactone,

b) halo,

c) C₁₋₆ alkoxy, C₁₋₆ alkylthio, C₁₋₆ alkyl, or C₁₋₆ haloalkyl,

d) CN,

e) N₃,

f) CO₂H,

g) CO₂—C₁₋₄ alkyl,

h) C(Y)(Z)—OH,

i) C(Y)(Z)—O—C₁₋₄ alkyl,

j) C₁₋₆ alkyl-CO₂—Y, or

k) ═O or ═S,

 wherein Y and Z are each independently H or C₁₋₆ alkyl, and wherein R⁷can be at any of positions 2-5.

Compounds according to Formulas I and II can be synthesized using knownprocedures from commercially available starting materials (see, e.g.,Dominianni et al., J. Org. Chem., 42, 344-46 (1977); Baek et al., Arch.Pharm. Res., 19, 228-30 (1996); Guthrie et al., J. Org. Chem. 47,2369-76 (1982)). For example, acid catalyzed condensation of2,6-dimethoxyphenol with OH—R³ can produce a 4-alkylphenol intermediate.Conversion of the phenolic group to the diethylphosphate ester followedby reduction with lithium metal in liquid ammonia can then produce adimethoxybenzene derivative. Mono- or didemethylation of this compound(e.g., with boron tribromide) can then yield the desired methoxyphenoland/or resorcinol (Formula I), respectively. Compounds of Formula Ihaving alkyl substituents at R⁶ can be prepared, for example, first bylithiation of the dimethoxybenzene derivative at R⁶ (e.g., in thepresence of Bu/THF) and subsequent exposure to an alkylating agent(e.g., methyl or ethyl iodide or sulfate). Mono- or didemethylation ofthis compound (e.g., with boron tribromide) can then yield the desiredmethoxyphenol and/or resorcinol (Formula I), respectively, having thealkyl substituents at R⁶. Compounds of Formula II can be prepared, forexample, by acid catalyzed condensation of a methoxyphenol and/orresorcinol (Formula I) having a desired substituents at R³ with geraniol(e.g., in the presence of BF₃, Et₂O, silica, and CH₂Cl₂). Of course,these compounds can be synthesized by other appropriate methods, many ofwhich are known in the art.

In another embodiment, at least one compound within thepharmacologically-acceptable composition is a cannabinol derivativehaving the following formula:

wherein,

R¹ is:

a) H,

b) a C₁₋₄ alkyl group or ester thereof,

c) COOH,

d) OH,

e) a O—C₁₋₅ alkyl (ether) or alkanoyl, optionally substituted by mono-or di-methylamino or ethylamino groups.

f) a O—CO—C₃₋₁₀ alkyl group containing a carboxyl or amino group,

g)

 wherein n=1 to 8, or

h) a p-aminobenzyl group or a C₁₋₇ aminoalkyl group or an organic ormineral acid addition salt thereof, an isocyanate or isothiocyanatederivative of the p-aminobenzyl or aminoalkyl group, a carboxylterminated derivative of the aminoalkyl group having from 1 to 7additional carbon atoms or a salt thereof, and an activated derivativeof the carboxyl terminated derivative;

i) R¹ and R² comprise a substituent of the formula —O(CH₂)₃₋₅, whereinR¹ and R², together with the carbon atoms to which they are bonded,comprises a ring where at least one hydrogen atom thereof is optionallysubstituted with a halogen.

R² is:

a) H, OH, or a halogen

b) C₁₋₆ carboxy or alkoxy (preferably methoxy) group, or

c) R¹ and R² comprise a substituent of the formula —O(CH₂)₃₋₅—, whereinR¹ and R², together with the carbon atoms to which they are bonded,comprises a ring where at least one hydrogen atom thereof is optionallysubstituted with a halogen.

R³ is:

a) (W)_(m)—Y—(Z)_(n), wherein

W is a C₅₋₁₂ alkyl, alkenyl, alkynyl, group, or mixture thereof,optionally substituted with at least one halogen,

Y is a bond, O, S, SO, SO₂, CO, NH, N(C₁₋₆ alkyl), or NCS,

Z is:

i) a C₅₋₁₂ alkyl, alkenyl, alkynyl, group, or mixture thereof,optionally substituted with at least one halogen, optionally substitutedwith a terminal aromatic ring,

ii) CN₁₋₃, NCS, CO₂H, or CO₂C₁₋₄ alkyl, CONH₂, CONHC₁₋₄ alkyl, orCON(C₁₋₄ alkyl)₂, wherein each C₁₋₄ alkyl on the amide nitrogen can bethe same or ditferent, or

iii) a phenyl or benzyl group, optionally substituted with halo, C₁₋₆alkyl, C₁₋₆ alkoxy, C₁₋₆ alkyltio, CN, CF₃, CO₂H, or CO₂C₁₋₄ alkyl,CONH₂, CONHC₁₋₄ alkyl, or CON(C₁₋₄ alkyl)₂, wherein each C₁₋₄ alkyl onthe amide nitrogen can be the same or different, and wherein

m and n are the same or different, and each is either 0 or 1,

b) a C₅₋₁₂ alkyl or haloalkyl group, optionally substituted with aterminal aromatic ring, CN₁₋₃, NCS, CO₂H, or CO₂C₁₋₄ alkyl, CONH₂,CONHC₁₋₄ alkyl, or CON(C₁₋₄ alkyl)₂, wherein each C₁₋₄ alkyl on theamide nitrogen can be the same or different, or

c) a C₅₋₁₂ alkene or alkyne group, optionally substituted with ahalogen, ditholene, terminal aromatic ring, CN₁₋₃, NCS, CO₂H, or CO₂C₁₋₄alkyl, CONH₂, CONHC₁₋₄ alkyl, or CON(C₁₋₄ alkyl)₂, wherein each C₁₋₄alkyl on the amide nitrogen can be the same or different,

R⁶ and R^(6′) together form ═O or ═S, or each is independently selectedfrom the group consisting of:

a) hydrogen,

b) C₁₋₆ alkoxy, C₁₋₆ alkylthio, C₁₋₆ alkyl, or C₁₋₆ haloalkyl,

c) CN,

d) CO₂H,

e) CO₂—C₁₋₄ alkyl,

f) C(Y)(Z)—OH,

g) C(Y)(Z)—O—C₁₋₄ alkyl, and

h) C₁₋₆ alkyl-CO₂—Y,

 wherein Y and Z are each independently H or C₁₋₆ alkyl

R⁷ is:

a) hydroxy or lactone,

b) halo,

c) C₁₋₆ alkoxy, C₁₋₆ alkylthio, C₁₋₆ alkyl, or C₁₋₆ haloalkyl

d) CN,

e) N₃,

f) CO₂H,

g) CO₂—C₁₋₄ alkyl,

h) C(Y)(Z)—OH,

i) C(Y)(Z)—O—C₁₋₄ alkyl

j) C₁₋₆ alkyl-CO₂—Y, or

k) ═O or ═S,

 wherein Y and Z are each independently H or C₁₋₆ alkyl;

Q is:

a) O or S, or

b) N—W, wherein W is:

i) hydrogen,

ii) C₁₋₆ alkoxyalkyl, C₁₋₆ alkyl, or C₁₋₆ haloalkyl

iii) OC₁₋₆ alkyl, or OC₁₋₆ haloalkyl,

iv) CN,

v) C₁₋₆ alkyl,

vi) C(Y)(Z)C₁₋₄ alkyl, or

vii) C₁₋₆ alkyl-CO₂—Z,

 wherein Y and Z are each independently H or C₁₋₆ alkyl.

It is known in the art that some compounds according to Formula III arepsychoactive, chiefly via agonism ofthe CB1 receptor. This, in someapplications, it may be preferable to employ substituents within FormulaIII (e.g., of R¹-R⁷, Q, and ring C) that preferably promote CB2 agonistactivity, rather than CB1 activity, and are more preferably substituentsthat promote selective CB2 agonist activity. In some embodiments, tomitigate or eliminate psychoactive effects attributed to somecannabinaoids, the inventive method employs a selective CB2 agonist,which is one that preferentially acts on the CB2 receptor, as opposed tothe CB1 receptor. Most preferably, the selective CB2 agonist does notbind the CB1 receptor at concentrations in which it activates the CB2receptor. Various selective CB2 agonists are known in the art. Examplesof such compounds include classical and nonclassical cannabinoids,bicyclic cannabinoids, aminoalkylindoles, and eicosanoids (see, e.g.,Pertwee, Pharmacol. Ther, 74(2), 129-80 (1997)). To assess whether agiven compound is a selective CB2 agonist, its relative affinity for theCB2 and CB1 receptors can be assessed using any suitable method, forexample using cells engineered to express the receptors (Ross et al.,Br. J. Pharmacol., 126, 665-72 (1999)). Such values typically areexpressed as a binding constant, K_(i), from which a ratio ofK_(i-CB1)/K_(i-CB2) can be calculated. Desirably, the selective CB2agonist has a K_(i) for the CB2 receptor of from about 100 nM to about0.1 nM, preferably from about 25 nM to about 0.2 nM, such as from about15 nM to about 0.5 nM. Moreover, the ratio of K_(i-CB1)/K_(i-CB2) is atleast about 1.5, and more preferably at least about 5 (e.g., at leastabout 10). Many compounds are known to have suitable CB2 selectivity foruse as a CB2 agonist in the inventive method. For example, JWH-015 has aK_(i-CB2) of 13.8±4.6 nN/I and a K_(i-CB1)/K_(i-CB2) ratio of 27.5;WIN-55,212-2 has a K_(i-CB2) of 0.028±0.16 nM and a K_(i-CB1)/K_(i-CB2)ratio of 6.75; 5-FΔB-THO has a K_(i-CB2) of 8.7±3.5 nM and aK_(i-CB1)/K_(i-CB2) ratio of 6.55; JWH-018 has a K_(i-CB2) of 2.94±2.65nM and a K_(i-CB1)/K_(i-CB2) ratio of 3.23; CP-56,667 has a K_(i-CB) ₂of 23.6±6.5 nM and a K_(i-CB1)/K_(i-CB 2) ratio of 2.61; L759656 has aK_(i-CB2) of 11.8±2.5 nM and a K_(i-CB1)/K_(i-CB2) ratio of 414.24; andL759633 has a KiCB₂ of 6.4±2.2 nM and a K_(i-CB1)/K_(i-CB2) ratio of162.97 (see above-referenced references). It is within the ordinaryskill in the art to assess these values for yet-unmeasured (or novel)compounds. Aside from binding the CB2 receptor preferentially, apreferred selective CB2 agonist exhibits greater CB2-directedphysiological response than CB1 response. A classic assay fordifferential activity measures the ability of a compound to inhibitdrug-induced cyclic AMP (cAMP) production in cells engineered to expressthe respective receptor. typically expressed as EC₅₀ (a percentage ofmaximal effects) (Ross et al., Br. J. Pharmacol., 126, 665-72 (1999)).Preferably, selective CB2 agonist typically exhibits aEC_(50-CB2)/EC_(50-CB1) ratio of greater than about 10, more typicallygreater than about 100 (e.g., greater than about 500). Many compoundsare known to have suitable CB2 selectivity, and thus can be used as aCB2 agonist in the inventive method. For example, L759656 has anEC_(50-CB2)/EC_(50-CB1) ratio of >3000; and L759633 has aEC_(50-CB2)/EC_(50-CB1) ratio of >1000. It is within the ordinary skillin the art to assess these values for yet-unmeasured (or novel)compounds.

For CB2 selectivity, R¹ in Formula III preferably is not OH, as it is inthe natural cannabinol and tetrahydrocannabinol compounds. Rather,preferably R¹ in Formula III is H, O—C₁₋₄ alkyl (more preferablymethoxy) or a hemi ester of succinic acid, malonic acid or the alaninateester of alanine and salts thereof. In another preferred embodiment, R¹and R² together comprise a substituent of the formula —O(CH₂)₃₋₅—,wherein R¹ and R², together with the carbon atoms to which they arebonded, comprise a ring where at least one hydrogen atom thereof isoptionally substituted with a halogen (e.g., an O,2 propano ring).Furthermore, where R² Formula III is a halogen, preferably it is iodo.Preferably, R⁶ and R^(6′) together form ═O or each are methyl, ethyl, ormethoxy.

While R⁷ can be at any of positions 7-10 of ring C, preferably it is atposition 9 of the ring. Where it is desired to promote CB2 selectivity,R⁷ preferably is electronegative (e.g., COOH. halogen, β-hydroxy, orlactone.), and to enhance activity, it can be substituted with either alactone or a β-hydroxy group.

Ring C in Formula III can be any of the following (the dashed linesrepresenting a double bond at either the Δ6a-10a, Δ8-9, or Δ9-10position):

However, to promote CB2 selectivity, preferably the ring is aromatic. Inthis regard, a preferred embodiment of the invention provides novelanti-viral cannabinol derivatives according to Formula III, wherein ringC is aromatic. In such compounds, R⁷ preferably is electronegative andmore preferably is on C9. Furthermore, R¹ preferably is other than OHand preferably is deoxy, an ester, or an ether. Exemplary cannabinolderivative compounds include:

Many compounds according to Formula III are well known, and others canbe manufactured in accordance with published methods (see, for example,International Patent Application WO99/20268 (Burstein), and U.S. Pat.No. 2,509,386 (Adams). U.S. Pat. No. 3,799,946 (Loev), U.S. Pat. No.3,856,821 (Loev), U.S. Pat. No. 3,897,306 (Vidic et al.), U.S. Pat. No.4,064,009 (Fukada et al.). U.S. Pat. No. 4,087,545 (Archer et al.), U.S.Pat. No. 4,142,139 (Bindra), U.S. Pat. No. 4,309,545 (Johnson), U.S.Pat. No. 4,599,327 (Nógráddi et al.), U.S. Pat. No. 4,833,073 (McNallyet al.), U.S. Pat. No. 4,876,276 (Mechoulan et al.). U.S. Pat. No.4,973,603 (Burstein), U.S. Pat. No. 5,338,753 (Burstein et al.), U.S.Pat. No. 5,389,375 (ElSohly), U.S. Pat. No. 5,440,052 (Makriyannis etal.). U.S. Pat. No. 5,605,906 (Lau), and U.S. Pat. No. 5,635,530(Mechoulam et al.), and Charalambous et al., Pharm. Biochem. Behav., 40,509-12 (191), Gareau et al., Bioorg. Med. Chem. Lett., 6(2), 189-94(1996), Griffin et al., Br. J. Pharmacol., 126, 1575-84 (1999), Huffmanet al., Bioorg. Med. Chem. Lett., 6, 2281-88 (1998), Lemberger et al.,Clin. Pharmacol. Ther., 18(6), 720-26 (1975), Loev et al., J. Med.Chem., 16(11), 1200-06 9 (1973). Loev et al., J. Med. Chem., 17(11),1234-35 (1974), Martin et al., Pharm. Biochem. Behav., 46, 295-301(1993), Papahatjis et al., J. Med. Chem., 41(7), 1195-1200(1998), Parset al., J. Med. Chem., 19(4), 445-53 (1976), Pertwee et al., Pharmacol.Ther., 74(2), 129-80 (1997), Razdan et al., J. Med. Chem., 19(4), 454-60(1976), Razdan, Pharmacol. Reviews, 38(2) 75-149 (1980), Reggio et al.,J. Med. Chem., 40(20), 3312-18 (1997). Reggio et al., Life Sci.,56(23124), 2025-32 (1995), (Ross et al., Br. J. Pharmacol., 126, 665-72(1999), Thomas et al., J. Pharm. Exp. Ther., 285(1), 285-92 (1998),Wiley et al., J. Pharm. Exp. Ther., 285(1), 995-1004 (1998), Winn etal., J. Med. Chem., 19(4), 461-71 (1976), and Xie et al., J. Med. Chem.,41, 167-74 (1998)).

In the preferred embodiment wherein ring C of Formula III is aromatic,such compounds additionally can be manufactured by aromatizing anappropriate tetrahydrocannabinol (THC) derivative molecule by knownmethods (see, e.g., Adams et al., J. Am. Chem. Soc., 62, 23401 (1940);Ghosh et al., J. Chem. Soc., 1393 (1940); and Adams et al., J. Am. Chem.Soc., 70, 664 (1948)). For example, aromatization of such compounds canoccur by heating the compound with sulfur at about 238-240° C., under anitrogen atmosphere, for about 4 hours (Rhee et al., J. Med. Chem.,40(20), 3228-33 (1997)). Other suitable methods include aromatizationusing a catalyst (e.g., palladium on carbon) or a chemicaldehydrogenating agent (e.g., 2,3-dichloro-5,6-dicyanoquinone) (see, forexample, U.S. Pat. No. 3,799,946 (Loev)).

As mentioned, in some applications of the inventive method, particularlywhere at least one of the compounds within the composition is acannabinol derivative, it is desirable to mitigate potentiallydeleterious psychoactivity attributed to some such compounds. As analternative to employing non-psychoactive cannabinol derivatives (e.g.,selective CB2 agonists) within the composition, otherpharmacologically-active agents can be employed in addition to mitigatepsychoactive effects. For example, as some of the aforementionedcompounds might exert some activity on CB1 receptors, it is oftendesirable to adjunctively administer a selective CB1 antagonist to thepatient. Indeed, in some applications it is desired to co-administer anon-selective CB2 agonist (e.g., Δ8- or Δ9-THC and derivatives thereof)in small doses, in which cases administration of a CB1 antagonist ispreferred. Many suitable selective CB1 antagonists are known in the art(Rinaldi-Carmona et al., FEBS Lett., 350, 240-44 (1994), see also U.S.Pat. No. 5,624, 941 (Barth et al.), U.S. Pat. No. 5,747,524 (Cullinan etal.), U.S. Pat. No. 5,925,768 (Barth et al.)). SR-1241716A is aparticularly potent, and theretofore preferred, selective CB1 antagonistfor use in the inventive method. Other preferred selective CB1antagonists are cannabidiol and its derivatives (see, e.g., U.S. Pat.No. 2,304,669 (Adams): Razdan et al., Pharmacol. Reviews, 38(2), 75-149(1986); Reggio et al., Life Sci., 56(23-24), 2025-32 (1995)), as thesepotently antagonize the CB1 receptor. In addition to antagonizing CB1,cannabidiol and many of its derivatives also advantageously attenuatethe cytochrome P₄₅₀ system in the liver, leading to enhancedbioavailability of other compounds within the composition (e.g.,Bormheim et al., Chem. Res. Toxicol., 11, 1209-16 (1998)). In thisregard, in some embodiments of the inventive method, at least onecompound within the pharmacologically-acceptable composition iscannabidiol or a derivative thereof having the following formula:

wherein:

R¹ is:

a) H,

b) a C₁₋₄ alkyl group or ester thereof

c) COOH,

d) OH,

e) a O—C₁₋₅ alkyl (preferably methoxy) or alkanoyl, optionallysubstituted by mono- or di-methylamino or ethylamino groups,

f) a O—CO—C₃₋₁₀ alkyl group containing a carboxyl or amino group,

 wherein n=1 to 8 or

h) a p-aminobenzyl group or a C₁₋₇ aminoalkyl group or an organic ormineral acid addition salt thereof, an isocyanate or isothiocyanatederivative of the p-aminobenzyl or aminoalkyl group, a carboxylterminated derivative of the aminoalkyl group having from 1 to 7additional carbon atoms or a salt thereof, and an activated derivativeof the carboxyl terminated derivative;

i) R¹ and R² comprise a substituent of the formula —O(CH₂)₃₋₅, whereinR¹ and R², together with the carbon atoms to which they are bonded,comprises a ring where at least one hydrogen atom thereof is optionallysubstituted with a halogen.

R² is:

a) H, OH or a halogen

b) C₁₋₆ carboxy or alkoxy group, or

c) R¹ and R² comprise a substituent of the formula —O(CH₂)₃₋₅, whereinR¹ and R², together with the carbon atoms to which they are bonded,comprises a ring where at least one hydrogen atom thereof is optionallysubstituted with a halogen.

R³ is:

a) (W)_(m)—Y—(Z)_(n), wherein

W is a C₅₋₁₂ alkyl, alkenyl, alkynyl, group, or mixture thereof,optionally substituted with at least one halogen,

Y is a bond, O, S, SO, SO₂, CO, NH, N(C₁₋₆ alkyl), or NCS,

Z is:

i) a C₅₋₁₂ alkyl, alkenyl, alkynyl, group, or mixture thereof,optionally substituted with at least one halogen, optionally substitutedwith a terminal aromatic ring,

ii) CN₁₋₃, NCS, CO₂H, or CO₂C₁₋₄ alkyl, CONH₂, CONHC₁₋₄ alkyl, orCON(C₁₋₄ alkyl)₂, wherein each C₁₋₄ alkyl on the amide nitrogen can bethe same or different, or

iii) a phenyl or benzyl group, optionally substituted with halo, C₁₋₆alkyl, C₁₋₆ alkoxy, C₁₋₆ alkyltio, CN, CF₃, CO₂H, or CO₂C₁₋₄ alkyl,CONH₂, CONHC₁₋₄ alkyl, or CON(C₁₋₄ alkyl)₂, wherein each C₁₋₄ alkyl onthe amide nitrogen can be the same or different, and wherein

m and n are the same or different, and each is either 0 or 1,

b) a C₅₋₁₂ alkyl or haloalkyl group, optionally substituted with aterminal aromatic ring, CN₁₋₃, NCS, CO₂H, or CO₂C₁₋₄ alkyl, CONH₂,CONHC₁₋₄ alkyl, or CON(C₁₋₄ alkyl)₂, wherein each C₁₋₄ alkyl on theamide nitrogen can be the same or different.

c) a C₅₋₁₂ alkene or alkyne group, optionally substituted with ahalogen, ditholene, terminal aromatic ring, CN₁₋₃, NCS, CO₂H or CO₂C₁₋₄alkyl, CONH₂, CONHC₁₋₄ alkyl, or CON(C₁₋₄ alkyl)₂, wherein each C₁₋₄alkyl on the amide nitrogen can be the same or different;

R ⁵is

a) H

b) a C₁₋₄ alkyl group

c) COOH

d) OH, or

e) a O—C₁₋₅ alkyl (ether) or alkanoyl optionally substituted with atleast one mono- or di-methylamino or ethylamino group;

R⁶ is:

a) hydrogen,

b) C₁₋₆ alkoxy, C₁₋₆ alkylthio, C₁₋₆ alkyl, or C₁₋₆ haloalkyl,

c) CN,

d) CO₂H,

e) CO₂—C₁₋₄ alkyl,

f) C(Y)(Z)—OH,

g) C(Y)(Z)—O—C₁₋₄ alkyl, or

h) C₁₋₆ alkyl-CO₂—Y,

 wherein Y and Z are each independently H or C₁₋₆ alkyl,

R⁷ is:

a) hydroxy or lactone,

b) halo,

c) C₁₋₆ alkoxy, C₁₋₆ alkylthio, C₁₋₆ alkyl, C₁₋₆ carboxy, or C₁₋₆haloalkyl,

d) CN,

e) N₃,

f) CO₂H,

g) CO₂—C₁₋₄ alkyl,

h) C(Y)(Z)—OH,

i) C(Y)(Z)—O—C₁₋₄ alkyl,

j) C₁₋₆ alkyl-CO₂—Y, or

k) ═O or ═S,

 wherein Y and Z are each independently H or C₁₋₆ alkyl, and wherein R⁷can be at any of positions 1, 2, 5, or 6 of ring C.

In addition to having the indicated substituents, R³ in any of formulasI-IV preferably is:

wherein W₁ is H, methyl, or ethyl, wherein W₂ and W₃ are eachindependently H or methyl, wherein at least one of W₁, W₂, and W₃ isother than H and/or halogenated, and wherein W₄ is a C₁₋₄ alkyl orhaloalkyl, optionally substituted with an aromatic ring. Preferably, R³is a branched C₆₋₁₂ alkyl group containing at least one double bond(more preferably at position C₄-C₁₀), and preferably the chain has anodd number of carbon atoms. More preferably, R³ is terminally branchedor contains a terminal double bond, and the invention provides compoundsaccording to Formulas I-IV having such substituents. More preferably, R³preferably is dimethylheptyl (DMH) (e.g., 1′,1′ DMH or 1′R, 2′S DMH),dimethylhexyl, or dimethylpentyl. For example, R³ can be a di- tri- ortetramethylpentyl, -hexyl, or -heptyl, etc., chain (e.g.,1,1,5-trimethylhexyl, 1,1,5,5-tetramethylhexyl, or1,1,5-trimethyl-hept-4-enyl). In some instances, the R³ substituent canhave bulky terminal moieties, for example, methyl, dimethyl,(CH₂)₆—CON(CH₃)₂, or C₆₋₁₂ haloalkyl with halogenated terminal carbonatoms (preferably bromine).

In the context of this invention, halogenated alkanes, alkenes, andalkynes can have any number of halogen substitutions. In a preferredembodiment, the halogenated alkane, alkene, or alkyne has at least onehalogen on a terminal carbon atom (e.g., CX₁₋₃, wherein X is halogen).Alkyl groups (as well as alkenes and alkynes) can be straight chain orbranched. Moreover, the compounds can exist as a single stereoisomer ora mixture of stereoisomers (e.g., a racemic mixture), or a singlegeometric isomer (e.g., E, Z, cis or trans) or a mixture of geometricisomers, all of which are within the scope of the invention.

In carrying out the inventive method, the composition can be deliveredto a patient in any amount and over any time course suitable forproducing the desired therapeutic effect, and one of skill in the artwill be able to determine an acceptable dosing schedule. For example,where the method is employed to treat HIV disease, an optimal dosage canbe assessed by assaying the number of circulating viral particles (viralload) and/or CD4+ cell count in response to increasing dosage.Typically, the composition is delivered to a patient between 1 and about6 times a day, if not continuously through transdermal or time releaseformulations. However, in some applications, it is appropriate toadminister the composition less often. Generally each dose is betweenabout 2 mg/m3 to about 1000 mg/m3, and more preferably about 0.01mg/kg/day, about 1 mg/kg/day, such as about 10 mg/kg/day to about 10mg/kg/day, and can be up to about 100 mg/kg/day (e.g., about 250mg/kg/day). These dosages can be somewhat reduced when the compositionis employed in combination with other agents, and especially when thecytochrome P₄₅₀ system is attenuated (e.g., through cannabidiolderivatives), as discussed herein. Moreover, where a selective CB1antagonist is employed, it can be administered in the same dose orcomposition as the inventive composition or in a different formulationor dosing schedule. In some applications, it is preferable to beginadministering the selective CB1 antagonist prior to (e.g., at least 1-4days prior to) the composition, to further minimize any residualactivation of the CB1 receptor and to prevent degradation of thecompound(s) within the composition. Of course, as some patients candevelop tolerance to one or more compounds within the composition overthe course of treatment, the dosage amount and/or schedule can beadjusted as appropriate. Moreover, the dosage amount and schedule can bereduced as a patient responds favorably to treatment and/or if any toxicside effects are noted.

By virtue of its many effects, the method can be employed to treat manydiseases or disorders associated with immune dysfunction in addition toHIV disease. For example, the method can treat autoimmune diseases(e.g., systemic lupus-erythrematosis, Hashimoto's thyroiditis,myasthenia gravis, rheumatoid arthritis, multiple sclerosis,Guillan-Barre syndrome, glomerulonephritis, etc.). The method can alsotreat diseases causing or depending on inflammatory conditions (e.g.,Crohn's disease, ulcerative colitis, forms of asthma), and it isparticularly effective in combating many neoplastic diseases, microbial(e.g., mycobacterial, fungal) infections, or viral infections,especially HSV, Epstein-Barr virus, Cytomegalovirus, HIV, and hepatitisB and C). The method also can treat abnormal immune responses, abnormalscar formation (e.g., surgical adhesions or keloids), allograftrejection, atherosclerosis and associated heart diseases. Of course, thepatient can be any sort of animal (e.g., a monkey, cat, dog, horse, cow,pigs, goat, and sheep, etc.).

Of course, where the method is employed to combat a disease associatedwith immune dysfunction, other appropriate therapeutic agents can beadjunctively employed as well. For example, the method can include theadjunctive administration of antineoplastics, antitumor agents,antibiotics, antifungals, antivirals (particularly antiretroviralcompounds), antihelminthic, and antiparasitic compounds. Exemplaryantiviral agents suitable for adjunctive use in the inventive methodinclude abacavir, azidothymidine cidofovir, delavirdine mesylate,didanosine, dideoxycytidine, efavirenz, foscarnet, ganciclovir,indinavir sulfate, lamivudine, nelfinavir mesylate, nevirapine,ritonavir, saquinavir, saquinavir mesylate, stavudine, zalcitabine, etc.In treating tumors or neoplastic growths, suitable adjunctive compoundscan include anthracycline antibiotics (such as doxorubicin,daunorubicin, carinomycin, N-acetyladriamycin, rubidazone,5-imidodaunomycin, and N-acetyldaunomycin, and epirubicin) and plantalkaloids (such as vincristine, vinblastine, etoposide, ellipticine andcamptothecin), paclitaxel and docetaxol, mitotane, cisplatin,phenesterine, etc. Anti-inflammatory therapeutic agents suitable foradjunctive use in the present invention include steroids andnon-steroidal anti-inflammatory compounds, (such as prednisone,methyl-prednisolone, paramethazone, 11-fludrocortisol orfluorocortisone, triamciniolone, betamethasone and dexamethasone,ibuprofen, piroxicam, beclomethasone, methotrexate, azaribine,etretinate, anthralin, psoralins); salicylates (such as aspirin; andimmunosuppresant agents such as cyclosporine). Additional pharmacologicagents suitable for adjunctive use in the inventive method includeanesthetics (such as methoxyflurane, isoflurane, enflurane, halothane,and benzocaine); antiulceratives (such as cimetidine); antiseizuremedications (such as barbituates; azothioprine (an immunosuppressant andantirheumatic agent); and muscle relaxants (such as dantrolene anddiazepam). Moreover, the method can be employed in conjunction withspecific antibody therapies or steroid therapies in treating autoimmunediseases. Other pharmacologically-active agents that can be adjunctivelyemployed in conjunction with the composition include other constituentsof natural marijuana having antimicrobial or anti-inflammatoryactivities (e.g., cannabigerol and its derivatives, cannabichromine andits derivatives, cannabinolic acid and its derivatives, cannabidiolicacid and its derivatives, terpenoids, flavanoids (e.g., cannflavin),etc.).

The composition can include biologically active agents, such aslymphokines or cytokines, anti-inflammatory, anti-bacterial, anti-viral,anti-fungal, anti-parasitic, anti-metabolic, anti-inflammatory,vasoactive, anti-neoplastic, bronchoacting, local anesthetic,immunomodulating, enzymatic, hormonal, growth promoting and regeneratingagents, as well as neurotransmitters, and cell receptor proteins andligands, among many other agents. Examples of other biological agentsare analgesics (such as acetominophen, anilerdine, aspirin,buprenorphine, butabital, butorphanol, choline salicylate, codeine,dezocine, diclofenac, diflunisal, dihydrocodeine, elcatonin, etodolac,fenoprofen, hydrocodone, hydromorphone, ibuprofen, ketoprofen,ketorolac, levorphanol, magnesium salicylate, meclofenamate, mefenamicacid, meperidine, methadone, methotrimeprazine, morphine, nalbuphine,naproxen, opium, oxycodone, oxymorphone, pentazocine, phenobarbital,propoxyphene, salsalate, sodium salicylate, tramadol and narcoticanalgesics in addition to those listed above). Anti-anxiety agents arealso useful including alprazolam, bromazepam, buspirone,chlordiazepoxide, chlormezanone, clorazepate, diazepam, halazepam,hydroxyzine, ketaszolam, lorazepam, meprobamate, oxazepam and prazepam,among others. Other biologically-active agents include anti-anxietyagents associated with mental depression, such as chlordiazepoxide,amitriptyline, loxapine, maprotiline, and perphenazine, among others.Examples of other active ingredients include anti-inflammatory agentssuch as non-rheumatic aspirin, choline salicylate, diclofenac,diflunisal, etodolac, fenoprofen, floctafenine, flurbiprofen, ibuprofen,indomethacin, ketoprofen, lidomide, magnesium salicylate, meclofenamate,mefenamic acid, nabumetone, naproxen, oxaprozin, phenylbutazone,piroxicam, salsalate, sodium salicylate, sulindac, tenoxicam,tiaprofenic acid, thalidomide, linomide, and tolmetin, as well asanti-inflammatories for ocular treatment (such as diclofenac,flurbiprofen, indomethacin, ketorolac, and rimexolone (generally forpost-operative treatment)), and anti-inflammatories for non-infectiousnasal applications (such as beclomethaxone, budesonide, dexamethasone,flunisolide, triamcinolone, and the like); soporifics(anti-insomnia/sleep inducing agents) such as those utilized fortreatment of insomnia, including alprazolam, bromazepam, diazepam,diphenhydramine, doxylamine, estazolam, flurazepam, halazepam,ketazolam, lorazepam, nitrazepam, prazepam quazepam, temazepam,triazolam, zolpidem and sopiclone, among others; sedatives includingdiphenhydramine, hydroxyzine, methotrimeprazine, promethazine, propofol,melatonin, trimeprazine, and the like; sedatives and agents used fortreatment of petit mal seizures and tremors, among other conditions,such as amitriptyline HCl; chlordiazepoxide, amobarbital; secobarbital,aprobarbital, butabarbital, ethchlorvynol, glutethimide, L-tryptophan,mephobarbital, methohexital sodium salt, midazolam HCl, oxazepam,pentobarbital Na, Phenobarbital, secobarbital sodium salt, thiamylalsodium, and many others. Other active compounds can include agents usedin the treatment of head trauma (brain injury/ischemia), such asenadoline HCl (e.g., for treatment of severe head injury),cytoprotective agents, and agents for the treatment of menopause,menopausal symptoms (treatment), e.g., ergotamine, belladonna alkaloidsand phenobarbital, for the treatment of menopausal vasomotor symptoms,e.g., clonidine, conjugated estrogens and medroxyprogesterone,estradiol, estradiol cypionate, estradiol valerate, estrogens,conjugated estrogens, esterified estrone, estropipate, and ethinylestradiol. Examples of agents for treatment of pre menstrual syndrome(PMS) are progesterone, progestin, gonadotrophic releasing hormone, oralcontraceptives, danazol, luprolide acetate, vitamin B6; agents fortreatment of emotional/psychiatric treatments such as tricyclicantidepressants including amitriptyline HCl (Elavil), amitriptyline HCl,perphenazine (Triavil) and doxepin HCl (Sinequan). Examples oftranquilizers, anti-depressants and anti-anxiety agents are diazepam(Valium), lorazepam (Ativan), alprazolam (Xanax), SSRI's (selectiveSeratonin reuptake inhibitors), fluoxetine HCl (Prozac), sertaline HCl(Zoloft), paroxetine HCl (Paxil), fluvoxamine maleate (Luvox)venlafaxine HCl (Effexor), serotonin, serotonin agonists (Fenfluramine);antibiotics (e.g., fluoroquinolones and tetracycline), antihistamines;catabolic steroids; and vasoactive agents (e.g., beta-blockers andpentoxiphylline (Trental)). Other compounds include cannabinoids such asCT-3 and HU-210.

As mentioned, for use in the inventive method, the compound(s) areincorporated into a pharmacologically-acceptable composition including asuitable carrier, and optionally other inactive or active ingredients.Such compositions are suitable for delivery by a variety ofcommonly-employed routes of delivery, such as, for example, buccal,sublingual, dermal, intraocular, intraotical, pulmonary, transdermal,intralymphatic, intratumor, intracavitary, intranasal, subcutaneous,implantable, inhalable, intradermal, rectal, vaginal, transmucosal,intramuscular, intravenous and intraarticular routes, among many others.Depending on the desired manner of application, the composition caninclude adjuvants, bile salts, biodegradable polymers and co-polymers,buffers, chelating agents, colorants, diluents, emollients, emulsifiers,enzyme inhibitors, hydrogels, hydrophilic agents, lipoproteins and otherfatty acid derivatives, liposomes and other micelles, microporousmembranes, mucoadhesives, neutral and hydrophobic polymers andco-polymers, particulate systems, perfumes, salt forming acids andbases, semi-permeable membranes, single or multiple enteric coatings,solvents (e.g., alcohols, dimethyl sulfoxide (DMSO), etc.), surfactants,viral envelope proteins, or other ingredients.

In one of its forms, the composition can be an inhalable formulationcomprising an aerosol of liquid or solid particles, such as are known inthe art. Application of the composition via inhalation can treatbronchial conditions associated with inflammation (e.g., the common cold(rhinovirus), influenza, cystic fibrosis, etc.). This formulation canfurther comprise additional agents such as preservatives, antioxidants,flavoring agents, volatile oils, buffering agents, dispersants,surfactants, and the like, as are known in the art. Such formulation canalso be provided with an inhalant, or in the inhalant, either in unitform or in a form which permits its repetitive use.

The composition can also be a topical formulation (e.g., ointment,cream, lotion, paste, gel, spray, aerosol oil, etc.), wherein thecarrier is a diluent for the agent suitable for topical delivery, e.g.,petrolatum, lanoline, polyethylene glycols, alcohols and the like,optionally including trans-dermal enhancers. In the topical formulation,the carrier may be in a form suitable for formulating creams, gels,ointments, sprays, aerosols, patches, solutions, suspensions andemulsions.

The composition can also be formulated for oral delivery, for example inthe form of capsules, cachets, lozenges, tablets, powder, granules,solutions, suspensions, emulsions, essential oils (particularly hempseed oil), etc. Such formulations typically include aqueous ornon-aqueous liquid solutions and suspensions (e.g., oil-in-water orwater-in-oil emulsions). Such oral formulations typically are encased inan enteric coating. Examples of oral formulations are buccal orsub-lingual formulation comprising lozenges which can also compriseflavoring agents and other known ingredients, or pastilles which canalso comprise an inert base containing, for example, gelatin, glycerin,sucrose, acacia, and other ingredients and fillers as is known to thepractitioner.

The composition can also be a parenteral formulation, such as injectablesolutions and suspensions. Typically, such formulations also compriseagents such as antioxidants, buffers, anti-bacterial agents, otheranti-viral agents such as direct acting inhibitors of replication, andsolutes which render the solution or suspension isotonic with the bloodof an intended recipient. The solutions or suspensions are typicallysterile aqueous or non-aqueous injectable solutions or suspensions, andcan also comprise suspending agents and thickening agents. Thisformulation is generally provided in a sealed ampule or vial.

The composition can also be a slow release formulation, which, whenadministered or applied to a subject, is capable of releasing a desiredamount of the compound(s) over a pre-determined period of time.Alternatively, the composition can be a transdermal formulation, inwhich the carrier is suitable for facilitating the transdermal deliveryof the agent. Examples are aqueous and alcoholic solutions, DMSO, oilysolutions and suspensions, and oil-in-water or water-in-oil emulsions. Atransdermal formulation can also be an iontophoretic transdermalformulation, in which typically the carrier can be an aqueous and/oralcoholic solution, an oily solution or suspension and an oil-in-waterand water-in-oil emulsion. This formulation can further comprise atransdermal transport promoting agent, and be provided in the form of akit with a transdermal delivery device, preferably an iontophoreticdelivery device, many variations of which are known in the art.

Additional formulations of the composition include, but are not limitedto an implantable capsule or cartridge (e.g., for tissue implantation),a patch, an implant, or a suppository (e.g., for rectal or transmucosaladministration).

Typically, the composition will be distributed, either to physicians orto patients, in an administration kit, and the invention provides suchan immunomodulating kit. Typically, such kits include, in separatecontainers, an administration device (e.g., syringes and needles,inhalators, pills, suppositories, transdermal delivery devices, etc) anda plurality of unit dosages of the composition as described above. Insome kits, the composition can be preformulated. Other kits includeseparate ingredients for formulating the composition. The kit canadditionally comprise a carrier or diluent, a case, and instructions forformulating the composition (if applicable) and for employing theappropriate administration device.

As mentioned, compounds according to Formula I have antineoplastic orcytotoxic activity, and the invention provides a method of inhibitingthe growth of a neoplasm (e.g., a neoplastic cell or tumor), comprisingdelivering such a compound to the neoplasm under conditions sufficientfor the growth of the neoplasm to be inhibited. Without being bound byany particular theory, 5-alkyl-resorcinols can cause DNA cleavage, whichcan potentially induce apoptosis within neoplastic cells. In thisregard, preferably the alkylated resorcinol derivative is delivered tothe neoplasm under conditions sufficient to potentiate apoptosis. Theexact dosing schedule needed to induce apoptosis will depend on the typeof compound employed, and whether additional compounds are alsoemployed. In this regard, the method can be delivered adjunctively, inconjunction with the delivery of at least one other antineoplastic agent(such as those set forth above).

In many applications, the method is employed in vivo (e.g., within apatient), such as within a tumor or blood dyscrasia. In some such invivo applications, the alkylated resorcinol derivative is delivered tothe neoplasm by introducing it into systemic circulation, such asthrough the gastric, intestinal, oral, or rectal wall or via intravenousinjection. In still other applications where the neoplasm is orcomprises a tumor, the alkylated resorcinol derivative can be deliveredby intratumoral injection. Such mode of delivery can, in some instances,increase the potential local concentration of the compound. For such invivo applications, the compound can be formulated into apharmacologically-acceptable composition as indicated herein, asappropriate.

The method can be employed to combat tumor growth, which, whilepreferable, need not result in elimination of the tumor or decrease intumor mass. In this regard, the method can be employed to attenuatetumor growth. Such an effect can, for example, make otherwise resistantneoplastic cells more susceptible to other antineoplastic agents, andthe method contemplates the adjunctive use of such other compounds, manyof which are known in the art (e.g., aldesleukin, altretamine,amifostine, asparaginase, azathioprine, bicalutamide, bicalutamide,bleomycin, busulfan, capecitabine, carboplatin, carmustine,chlorambucil, cisplatin injection, cladribine, cyclophosphamide,cyclosporine o, cytarabine, cytarabine liposome injection, dacarbazine,dactinomycin, daunorubicin, denileukin diftitox, dexrazoxane, docetaxel,doxorubicin, doxorubicin hydrochloride, estramustine phosphate sodium,etoposide, etoposide phosphate, floxuridine pegaspargase, fludarabinephosphate, flutamide, gemcitabine HCl, goserelin, granisetronhydrochloride, hydroxyurea, idarubicin hydrochloride, ifosfamide,interferon alfa-2a, recombinant, interferon alfa-2b, irinotecanhydrochloride, leucovorin, leuprolide acetate, levamisole, lomustine,L-PAM, L-phenylalanine mustard, mechlorethamine, melphalan,mercaptopurine, methotrexate, mitomycin, mitotane, mitoxantronehydrochloride, nilutamide, nilutamide, octreotide, ondansetronhydrochloride, paclitaxel, pamidronate disodium, pentostatin,phenylalanine mustard, plicamycin, polifeprosan 20 with carmustineimplant, porfimer sodium, procarbazine HCl, rituximab, sargramostim,streptozocin 2-deoxy-2-[[(methylnitrosoamino), tamoxifen citrate,teniposide, testolactone, thioguanine, thiotepa for injection, topotecanhydrochloride, toremifene citrate, trastuzumab, tretinoin, trimetrexateglucuronate, valrubicin, vinblastine sulfate, vincristine sulfate,vinorelbine tartrate, etc.). Moreover, even where tumor growthcontinues, such attenuation is useful for slowing the progress of thedisease, thus permitting greater time for other therapeutic approaches.Indeed, combination therapy may allow for smaller or greater doses ofother such antineoplastic agents for shorter or longer durations, thuspotentially facilitating increased efficacy and potentially reducingside effects.

EXAMPLES

While one of skill in the art is fully able to practice the instantinvention upon reading the foregoing detailed description, the followingexamples will help elucidate some of its features. Of course, as theseexamples are presented for purely illustrative purposes, they should notbe used to construe the scope of the invention in a limited manner, butrather should be seen as expanding upon the foregoing description of theinvention as a whole.

Example 1

This example demonstrates the synthesis of a compound according toFormula I.

A mixture of 2,6-dimethoxyphenol (73.4 g, 0.48 mole),2,6-dimethyl-2-heptanol (69.0 g, 0.48 mole) and methanesulfonic acid (95mL) was stirred at 50° C. for 3 h and then at room temperatureovernight. The mixture was poured over ice-water (600 mL) with stirring.The mixture was extracted with CH₂Cl₂ (2×200 mL). The extracts werewashed with water, saturated aqueous NaHCO₃, saturated aqueous sodiumchloride solution and dried over anhydrous Na₂SO₄. The solution wasconcentrated under reduced pressure to obtain the product as an oil (130g, 96%). Analysis of this substance (MS (FAB) m/z 281 (MH)⁺; ¹H NMR(CDCl₃) δ 0.80 (d, 6H), 1.0-1.1 (m, 4H), 1.27 (s, 6H), 1.40-1.60 (m,3H), 3.89 (s, 6H), 5.36 (s, 1H), 6.54 (s, 2H), 1.0-1.1 (m, to be4-(1,1,5-trimethylhexyl)-2,6-dimethoxyphenol:

Example 2

This example demonstrates the synthesis of a compound according toFormula I.

A solution of crude 4-(1,1,5-trimethylhexyl)-2,6-dimethoxyphenol fromExample 1 (130 g, 0.46 mole) in dry CCl₄ (100 mL) was cooled in ice-bathand diethyl phosphite (70 mL, 0.54 mole) was added. To the stirredmixture triethylamine (75 mL, 0.54 mole) was added dropwise at such arate as to maintain the temperature of the reaction mixture below 10° C.The reaction mixture was stirred in the ice-bath for 2 h and at roomtemperature overnight. The mixture was then diluted with CH₂Cl₂ (200mL), washed with water, 4N aqueous NaOH (100 mL), 1N aqueous HCl (125mL), water and saturated aqueous sodium chloride solution. The extractswere dried over anhydrous Na₂SO₄ and concentrated under reducedpressure. The crude product was purified by chromatography over a columnof silica using cyclohexane:EtOAc (7:1 to 3:1 gradient) as the eluent toobtain 103 g (54%) of the product as a colorless waxy oil. Analysis ofthis substance (MS (FAB) m/z 417 (MH)⁺. ¹H NMR (CDCl₃) δ 0.81 (d, 6H),1.0-1.1 (m, 4H), 1.26 (s, 6H), 1.35-1.6 (m, 9H), 3.86 (s, 6H), 4.25-4.38(m, 4H), 6.53 (s, 2H)) revealed it to be4-(1,1,5-trimethylhexyl)-2,6-dimethoxyphenyl diethyl phosphate:

Example 3

This example demonstrates the synthesis of a compound according toFormula I.

A solution of 4-(1,1,5-trimethylhexyl)-2,6-dimethoxyphenyl diethylphosphate from Example 2 (82 g, 0.197 mole) in Et₂O (175 mL) and THF (35mL) was added slowly to liquid ammonia (450 mL) contained in a 3-neckvessel fitted with mechanical stirrer, thermometer, dry ice condenserand a pressure equalizing addition funnel while adding small freshly cutpieces of lithium wire (2.8 g, 0.40 g-atom) at such a rate as tomaintain a blue color. The reaction mixture was stirred further for anhour and then quenched by the addition of saturated aqueous NH₄Cl (22mL). Ether (220 mL) was added and the ammonia was allowed to evaporateovernight. The residue was treated with water (220 mL). The layers wereseparated and the ether layer was washed with 4N NaOH (200 mL), water(2×200 mL) and saturated aqueous sodium chloride solution. The organicextracts were dried (MgSO₄) and concentrated under reduced pressure. Thecrude product was purified by chromatography over a column of silicausing cyclohexane:EtOAc (95:5) as the eluent to obtain 43 g (83%) of theproduct as a colorless oil. Analysis of this substance (MS (FAB) m/z 265(MH)⁺; ¹H NMR (CDCl₃) δ 0.80 (d, 6H), 1.00-1.10 (m, 411), 1.26 (s, 6H),1.4-1.6 (m, 3H), 3.79 (s, 6H), 6.30 (m, 1H), 6.49 (m 2H)) revealed it tobe 4-(1,1,5-trimethylhexyl)-2,6-dimethoxybenzene:

Example 4

This example demonstrates the synthesis of a compound according toFormula I.

A solution of 4-(1,1,5-trimethylhexyl)-2,6-dimethoxybenzene from Example3 (10 g, 0.038 mole) in anhydrous CH₂C₂ (100 mL) was cooled in ice-bathand was treated dropwise with a solution of boron tribromide in CH₂Cl₂(100 mL of 1M solution, 0.10 mole) over a period of 1 h. The mixture wasstirred in the cold bath for 2 h and then at room temperature overnight.The reaction mixture was cooled in ice-bath and cautiously treated withwater (100 mL). The resulting mixture was diluted with CH₂Cl₂ (100 mL)and treated with half-saturated aqueous sodium bicarbonate solution. Thelayers were separated, the organic layer was concentrated to half volumeunder reduced pressure and extracted with 2N aqueous NaOH (2×75 mL). Theaqueous alkaline extract was cooled and acidified to pH 3.0 with 1Naqueous HCl. The acidified mixture was extracted with Et₂O (2×100 mL).The ether layer was washed with saturated aqueous sodium chloridesolution, dried over anhydrous MgSO₄ and concentrated under reducedpressure. The crude product thus obtained was purified by chromatographyover a column of silica using cyclohexane:EtOAc (8:1 to 4:1 gradient) asthe eluent to obtain 8.0 g (90%) of the product as colorless crystallinesolid. Analysis of this substance (Mp 95-96° C. MS (FAB) m/z 237 (MH)⁺;¹H NMR (CDCl₃) δ 0.80 (d, 6H), 1.00-1.10 (m, 4H), 1.23 (s, 6H),1.40-1.58 (m, 3H), 4.65 (s, 2H), 6.17 (m, 1H), 6.38 (m, 2H)) revealed itto be 4-(1,1,5-trimethylhexyl) resorcinol:

Example 5

This example demonstrates the synthesis of a compound according toFormula I.

A solution of 4-(1,1,5-trimethylhexyl) resorcinol from Example 4 (2 g,0.0076 mole) in anhydrous CH₂Cl₂ (10 mL) was cooled in ice-bath and wastreated dropwise with a solution of boron tribromide in CH₂Cl₂ (2.6 mLof 1M solution 0.0026 mole). The mixture was stirred in the cold bathfor 2 h and then at room temperature overnight. The mixture was cooledin ice-bath and cautiously treated with water (10 mL) followed bysaturated aqueous sodium bicarbonate (5 mL). The organic layer wasseparated, dried over MgSO₄ and concentrated under reduced pressure. Theresidue was purified by chromatography over a column of silica usingcyclohexane:EtOAc (8:1 to 4:1 gradient) as the eluent to obtain 0.364 g(19%) of the product as a colorless oil. Analysis of this substance (MS(FAB) m/z 251 (MH)⁺; ¹H NMR (CDCl₃) δ 0.80 (d, 6H), 1.00-1.10 (m, 4H),1.24 (s, 6H), 1.4-1.6 (m, 3H), 3.78 (s, 3H), 4.67 (s, 1H), 6.23 (m, 1H),6.40 (m, 1H), 6.47 (m, 1H)) revealed it to be3-methoxy-5-(1,1,5-trimethylhexyl)phenol:

Example 6

This example demonstrates the antiviral activity of several compoundsaccording to the invention.

Compounds.

Compounds indicated in Table 1 were prepared as varying concentrationsin SDMSA and used fresh.

Latently Infected Cells.

5×10³ U1 cells (obtained from the AIDS Research and Reference ReagentProgram, Bethesda, Md.) were plated in 96-well plates with media with orwithout 5 ng/ml TNFα and a test compound. After 3 to 6 days incubation,the supernatants and cells were assessed.

PBMC Isolation and Blasting.

Peripheral blood mononuclear cells (PBMC) obtained from healthy HIV- andhepatitis-negative patients were washed to remove residual gradientseparation material. The washed cells were then counted, and theirviability assessed. Following this initial preparation, the cells aresuspended in RPMI 1640 medium supplemented with 15% inactivated fetalbovine serum, 2 nM L-glutamine, 100 U/ml penicillin, 100 μg/mlstreptomycin, and 10 μg/ml gentamycin with 2 μg/ml PHA at 1×10⁶cells/ml. Following a 2 to 3 day incubation (37° C., 5% CO₂). the cellswere collected by centrifugation, washed, and resuspended in the samemedium, supplemented with recombinant IL-2. The cultures were thenmaintained until use by ½ volume change with fresh IL-12 containingmedium every 3 days.

PBMC Assay.

When ready for use, PBMCs from a minimum of two donors that have beenblasted with PHA and IL-1 were mixed, counted, and viability determinedby trypan blue exclusion. The cells were then resuspended in 1×10⁶cells/ml in RPMI 1640 supplemented with 15% fetal bovine serum (heatinactivated), 2 mM L-glutamine. 100 U/ml penicillin, 100 μg/mlstreptomycin, 10 μg/ml gentamycin and IL-2 (20 U/ml). 50 μl of cellswere then distributed to the inner 60 wells of a 96 well plate. Eachplate contains cell control wells (cells only), virus control wells(cells plus virus), drug toxicity control wells (cells plus testcompound), drug colorimetric control wells (drug only) as well asexperimental wells (drug plus cells plus virus). Diluted compounds werethen added to the microliter plate followed by the appropriatepre-titered strain of HIV-1. All samples were assayed in triplicate witha sister plate for the determination of compound toxicity. The finalvolume per well was 200 μl. The assay was incubated for 7 days at 37°C., 5% CO₂, after which supernatants were collected for analysis of RTactivity and sister plates for assessment of cell viability.

Monocyte Isolation and Culture.

Peripheral blood monocytes (PBM) were obtained from healthy HIV- andhepatitis-negative donors by ficoll hypaque purification (optionallyusing recombinant IFNγ. After 7 days, the cultures were washed to removenon adherent cells, and test compounds were added followed by HIV-1.Cultures were washed a final time by media removal 24 hours postinfection, fresh test compound was added, and the cultures continued foran additional seven days. Virus replication was then measured byexpression of supernatant p24 antigen by commercially available ELISAassays. AZT was used as a positive control run in parallel with eachdetermination.

XTT Staining for Viability.

Absence of toxicity was assessed by reduction of2,3-bis(2-methoxy-4-nitro-5-sulfophenyl)-5-[(phenylamino)carbonyl]2H-tetrazoliumhydroxide (XXT). 50 μl of a solution containing 1 mg/ml XTT and 0.06μg/ml phenazine methanesulfate (PMS) was added per well, and the platewas incubated for 4 hours at 37° C. Adhesive plate sealers were used inplace of the lids so that the sealed plates could be inverted severaltimes to mix the soluble reaction product. Following this incubation,the plates were read spectrophotometrically at 450 nm to assess thedegree of reduction product.

Analysis of p24.

Viral protein production (p24) was assessed by standard ELISA.

Reverse Transcriptase Assay.

HIV reverse transcriptase was measured in cell free supernatants.Titrated TTP was resuspended in distilled H₂O at 5 Ci/ml. Poly rA andoligo dT were prepared as a stock solution which was kept at −20° C. TheRT reaction buffer (125 μl 1 M EGTA, 125 μl dH₂O, 110 μl 10% SDS, 50 μl1M Tris (pH 7.4), 50 μl 1M DTT, and 40 Ml 1M MgCL₂) was prepared fresh.The three solutions were then mixed together in a ratio of 2 part TTP, 1part polyrA:oligo dT, and 1 part buffer. Ten μl of this reaction mixturewas then placed in a round bottom microliter plate, and 15 μl ofvirus-containing supernatant was added. The plate was incubated at 37°C. in a water bath with a solid support for 60 minutes. Following thereaction, the volume was spotted onto pieces of DE81 paper, washed 5times for 5 minutes each in a 5% sodium phosphate buffer, 2 times for 1minute in distilled water, 2 times for 1 minute each in 70% ethanol, andthen dried. Opti-Fluor O was then added to each sample and incorporatedradioactivity was quantified using a scintillation counter.

Data Analysis. IC₅₀ (i.e., 50% inhibition of virus replication), TC₅₀(50% cytotoxicity), and a selectivity index (SI=IC₅₀/TC₅₀) werecalculated for each assay. Pooled data for all compounds tested arepresented in Table 1. The results indicate that11-nor-Δ9-tetrahydrocannabidinol-9-carboxylic acid, cannabidiol, andolivitol, 5-(1,1,5-trimethylhexyl) resorcinol, and5-(1,1,5-trimethylhexyl)-2,6-dimethoxyphenol exhibited moderateantiviral activity. The antiviral activity of olivitol was morepronounced in the PBMCs and TNFα induced U1 cells than inmonocytes/macrophages or uninduced U1 cells. Particularly with referenceto the cannabinoids, these results are surprising, given observationsthat some such compounds can enhance, rather than suppress HIVreplication (see, e.g., Noe et al., Chapter 25 in Drug of Abuse,Immunomodllation and AIDS, Friedman et al., Ed., (Plenum Press, NY1998)).

Example 7

This example demonstrates the antineoplastic activity of compoundsaccording to Formula 1.

Cell Lines.

Cell lies indicated in table 2 wee propagated under sterile conditionsin RPMI 1640 or DMEM with 10% fetal calf serum, 2 mM L-glutamine, andsodium bicarbonate (“complete medium”) and incubated at 37° C. 5% CO₂and 95 % humidity. Each cell line was subcultured once or twice weekly,and the were periodically screened for mycoplama contamination(positivice cultures were cured over three passages with antibiotic).Only cultures free of mycoplasma were used for antineoplasticassessment.

Antineoplastic Assessment.

Cells from each cell line were harvested, pelleted to remove the media,and then suspended in fresh complete medium. The cell count wasdetermined and viability was measured with propidium iodide staining.The cells were adjusted with complete medium to a density of 5×10³cells/ml. Tissue culture plates were seeded with 100 μl samples of eachcell line, and they plates were incubated overnight to allow for cellanchorage and acclimation.

Following acclimation, the compounds indicated in table 2 were dilutedin complete medium. A range of eight concentrations was used to treatthe cell cultures. For each dilution, eight wells are each treated with100 μl of dosing solution. Each culture plate contains a cell control (8wells, mock treated with complete medium), a medium control (7 wellswith medium used to subtract out signal generated by media conditions),a solvent control (8 wells), and an air blank (1 well) for calibratingthe plate reader. Each cell line was also treated with a single dose ofdoxorubicin (1 μM, eight wells) as a positive control for cytotoxicity.Once dosing was completed, the cells were incubated at 37° C. in 5% CO₂and 95% humidity.

Five days after treatment, the cells were analyzed for antineoplasticeffects using the SRB assay to calculate IC₅₀ for each treatment. Theresults are presented in Table 2. The results indicate that5-(26-dimethyl-2-heptyl)resorcinol exhibited an IC₅₀ of 77-95 μM in sixcell lines, indicating that such compounds have antineoplastic effects.

INCORPORATION BY REFERENCE

All sources (e.g., inventor's certificates, patent applications,patents, printed publications, repository accessions or records, utilitymodels, world-wide web pages, and the like) referred to or citedanywhere in this document or in any drawing, Sequence Listing, orStatement filed concurrently herewith are hereby incorporated into andmade part of this specification by such reference thereto.

GUIDE TO INTERPRETATION

The foregoing is an integrated description of the invention as a whole,not merely of any particular element of facet thereof. The descriptiondescribes “preferred embodiments” of this invention, including the bestmode known to the inventors for carrying it out. Of course, upon readingthe foregoing description, variations of those preferred embodimentswill become obvious to those of ordinary skill in the art. The inventorsexpect skilled artisans to employ such variations as appropriate, andthe inventors intend for the invention to be practiced otherwise than asspecifically described herein. Accordingly, this invention includes allmodifications and equivalents of the subject matter recited in theclaims appended hereto as permitted by applicable law.

As used in the foregoing description and in the following claims,singular indicators (e.g., “a” or “one”) include the plural, unlessotherwise indicated. Recitation of a range of discontinuous values isintended to serve as a shorthand method of referring individually toeach separate value falling within the range, and each separate value isincorporated into the specification as if it were individually listed.As regards the claims in particular, the term “consisting essentiallyof” indicates that unlisted ingredients or steps that do not materiallyaffect the basic and novel properties of the invention can be employedin addition to the specifically recited ingredients or steps. Incontrast, the terms “comprising” or “having” indicate that anyingredients or steps can be present in addition to those recited. Theterm “consisting of” indicates that only the recited ingredients orsteps are present, but does not foreclose the possibility thatequivalents of the ingredients or steps can substitute for thosespecifically recited.

TABLE 1 Monocyte/macrophage assay with HIV-1 (p24) PBMC HIV-1 (RT) TNFinduced U1 cells (RT) Compound IC₅₀ TC₅₀ TI IC₅₀ TC₅₀ TI IC₅₀ TC₅₀ TIAZT (μM) 0.0021 >4 >1904 0.001 >4 >4000 0.0056 >4 714.2 — — — 0.0061 >4655.7 0.0034 >4 1176 0.099 >10 >101.0 DdC (μM) 0.0028 >10 >3,5710.0876 >10 114 — — — Cannabinol (μg/ml) 7.7 13.07 1.7 6.91 7.66 1.115.14 5.26 1.0 Cannabidiol (μg/ml) 8.18 22.87 2.8 1.52 7.76 5.11 2.76 7.82.8 11-nor-Δ9-tetrahydrocannabidinol-9- carboxylic acid (μg/ml) 7.7976.73 9.8 39.09 71.1 1.82 6.69 23.71 3.55 Δ8 tetrahydrocannabinol(μg/ml) >0.1 >0.1 NA 0.08 >0.1 >1.25 0.06 >0.1 >1.667 Δ9tetrahydrocannabinaol (μg/ml) >0.1 >0.1 NA 0.07 >0.1 1.43 0.06 0.0881.47 EtOH (%) 0.06 >.1 >1.67 >0.1 >0.1 NA >0.1 >0.1 NA Olivitol (μM)63.7 75.9 1.19 16.9 >100 5.9 22.5 77.5 3.45 Resorciol (μM) NA NANA >200 >200 — NA NA NA Orcinol (μM) NA NA NA >200 >200 — NA NA NA5-(1,1,5-trimethylhexyl) resorcinol (μM) NA NA NA 14.8 44.6 3 NA NA NA5-(1,1,5-trimethylhexyl)-2,6-dimethoxyphenol (μM) NA NA NA 15.8 50.9 3.2NA NA NA 5-(1,1,5-trimethylhexyl)-2,6- dimethoxybenzene (μM) NA NANA >200 >200 — NA NA NA 3-methoxy-5-(1,1,5-trimethylhexyl)phenol (μM) NANA NA 39.9 46.4 1.2 NA NA NA

TABLE 2 IC₅₀ Values in μg/ml (IC₅₀ Molar Values) SNB-7 DLD-1 NCI-H23ZR-75-1 LOX IMVI PC-3 CAKI-1 (CNS) (colon) (lung) (mammary) (melanoma)(prostate) (renal) 5-(2,6-dimethy-2-lheptyl)resorcinol 2.2 × 10¹  2.1 ×10¹  1.8 × 10¹  1.9 × 10¹  NA 2.0 × 10¹  2.2 × 10¹  (9.5 × 10⁻⁵) (9.0 ×10⁻⁵) (7.7 × 10⁻⁵) (8.1 × 10⁻⁵) (8.4 × 10⁻⁵) (9.3 × 10⁻⁵) olivetol 4.0 ×10¹  4.2 × 10¹  3.3 × 10¹  3.6 × 10¹  4.4 × 10¹  3.7 × 10¹  4.0 × 10¹ (2.2 × 10⁻⁴) (2.3 × 10⁻⁴) (1.8 × 10⁻⁴) (2.0 × 10⁻⁴) (2.4 × 10⁻⁴) (2.0 ×10⁻⁴) (2.2 × 10⁻⁴)

What is claimed is:
 1. An alkylated resorcinol derivative that hasfollowing formula:

wherein, R¹ is: OH, OCH₃ R² is: H R³ is: 1,1,5-trimethylhexyl,1,1,5,5-tetramethylhexyl, or 1,1,5-trimethyl-hept-4-enyl. R⁴ is: H R⁵is: OH, or OCH₃; and R⁶ is: H, OH, methyl, or ethyl.
 2. The alkylatedresorcinol of claim 1, wherein R¹ is OH.
 3. The alkylated resorcinol ofclaim 1, wherein R¹ is OCH₃.
 4. The alkylated resorcinol of claim 1,wherein R⁵ is OH.
 5. The alkylated resorcinol of claim 1, wherein R⁵ isOCH₃.
 6. The alkylated resorcinol of claim 1, wherein R⁶ is H.
 7. Thealkylated resorcinol of claim 1, wherein R⁶ is OH.
 8. The alkylatedresorcinol of claim 1, wherein R⁶ is methyl.
 9. The alkylated resorcinolof claim 1, wherein R⁶ is ethyl.
 10. The alkylated resorcinol of claim1, wherein R³ is 1,1,5-trimethylhexyl.
 11. The alkylated resorcinol ofclaim 10, wherein R¹ is OH.
 12. The alkylated resorcinol of claim 10,wherein R¹ is OCH₃.
 13. The alkylated resorcinol of claim 10, wherein R⁵is OH.
 14. The alkylated resorcinol of claim 10, wherein R⁵ is OCH₃. 15.The alkylated resorcinol of claim 10, wherein R⁶ is H.
 16. The alkylatedresorcinol of claim 10, wherein R⁶ is OH.
 17. The alkylated resorcinolof claim 10, wherein R⁶ is methyl.
 18. The alkylated resorcinol of claim10, wherein R⁶ is ethyl.
 19. The alkylated resorcinol of claim 1,wherein R³ is 1,1,5,5-tetramethylhexyl.
 20. The alkylated resorcinol ofclaim 19, wherein R¹ is OH.
 21. The alkylated resorcinol of claim 19,wherein R¹ is OCH₃.
 22. The alkylated resorcinol of claim 19, wherein R⁵is OH.
 23. The alkylated resorcinol of claim 19, wherein R⁵ is OCH₃. 24.The alkylated resorcinol of claim 19, wherein R⁶ is H.
 25. The alkylatedresorcinol of claim 19, wherein R⁶ is OH.
 26. The alkylated resorcinolof claim 19, wherein R⁶ is methyl.
 27. The alkylated resorcinol of claim19, wherein R⁶ is ethyl.
 28. The alkylated resorcinol of claim 1,wherein R³ is 1,1,5-trimethyl-hept-4-enyl.
 29. The alkylated resorcinolof claim 28, wherein R¹ is OH.
 30. The alkylated resorcinol of claim 28,wherein R¹ is OCH₃.
 31. The alkylated resorcinol of claim 28, wherein R⁵is OH.
 32. The alkylated resorcinol of claim 28, wherein R⁵ is OCH₃. 33.The alkylated resorcinol of claim 28, wherein R⁶ is H.
 34. The alkylatedresorcinol of claim 28, wherein R⁶ is OH.
 35. The alkylated resorcinolof claim 28, wherein R⁶ is methyl.
 36. The alkylated resorcinol of claim28, wherein R⁶ is ethyl.
 37. A method of inhibiting the growth of aneoplasm, comprising delivering an alkylated resorcinol derivative ofclaim 1 to the neoplasm such that the growth of the neoplasm isinhibited.
 38. The method of claim 37, wherein the alkylated resorcinolderivative potentiates apoptosis within cells of the neoplasm.
 39. Themethod of claim 37, wherein the alkylated resorcinol derivative isadjunctively delivered in conjunction with the delivery of at least oneother antineoplastic agent.
 40. The method of claim 37, wherein theneoplasm is within a tumor, and the method attenuates the growth of thetumor.
 41. The method of claim 37, wherein the neoplasm is within ablood dyscrasia, and the method attenuates the growth of the blooddyscrasia.
 42. The method of claim 37, wherein the neoplasm is in vivo.43. The method of claim 42, wherein the alkylated resorcinol derivativeis delivered to the neoplasm by introducing it into systemiccirculation.
 44. The method of claim 43, wherein the alkylatedresorcinol derivative is introduced into systemic circulation throughthe gastric intestinal, oral, or rectal wall or via intravenousinjection.
 45. The method of claim 42, wherein the alkylated resorcinolderivative is delivered to the neoplasm by intratumoral injection. 46.The method of claim 37, wherein R¹ of the alkylated resorcinol is OH.47. The method of claim 37, wherein R¹ of the alkylated resorcinol isOCH₃.
 48. The method of claim 37, wherein R³ of the alkylated resorcinolis 1,1,5-trimethylhexyl.
 49. The method of cliam 37, wherein R³ of thealkylated resorcinol is 1,1,5,5-tetramethylhexyl.
 50. The method ofclaim 37, wherein R³ of the alkylated resorcinol is1,1,5-trimethyl-hept-4-enyl.
 51. The method of claim 37, wherein R⁵ ofthe alkylated resorcinol is OH.
 52. The method of claim 37, wherein R⁵of the alkylated resorcinol is OCH₃.
 53. The method of claim 37, whereinR⁶ of the alkylated resorcinol is H.
 54. The method of claim 37, whereinR⁶ of the alkylated resorcinol is OH.
 55. The method of claim 37,wherein R⁶ of the alkylated resorcinol is methyl.
 56. The method ofclaim 37, wherein R⁶ of the alkylated resorcinol is ethyl.